There is a clear association between smoking and lung cancer, but it is still not known why some individuals, who are heavily exposed to large concentrations of chemical carcinogens, do not develop tumors, whereas others do. These observations provide circumstantial evidence for the involvement of a genetic factor that predisposes for tumor formation. Recent restriction fragment length polymorphism (RFLP) studies have shown that the loss of normal cellular sequences from chromosome 13 (in the case of retinoblastoma), chromosome 11 (in the case of Wilm's tumor and bladder cancer and breast cancer), chromosome 1 (in the cases of melanoma), chromosome 22 (in the case of acoustic neuroma) and chromosome 3 (in the case of small cell carcinoma of the lung) have been associated with malignancy. It appears that this method might be generally applied to the analysis of inherited susceptibility to cancer and therefore be informative in risk assessment for lung cancer. Tumor and normal tissue from high molecular weight DNA samples have been collected from more than 60 cancer patients for restriction enzyme digestion and Southern analysis. Initial experiments have centered on examination of genes located on the short-arm of chromosome 11; loss of allelic fragments during tumorigenesis have been detected at the cellular Harvey ras locus, the insulin locus, the calcitonin locus, the beta-globin locus, the catalase locus and the Int-2 locus (homologous to the MMTV locus). Experiments that examine additional loci throughout the human genome for these DNA samples are in progress.